Serpins in Hemostasis as Therapeutic Targets for Bleeding or Thrombotic Disorders

Abstract

Bleeding and thrombotic disorders result from imbalances in coagulation or fibrinolysis, respectively. Inhibitors from the serine protease inhibitor (serpin) family have a key role in regulating these physiological events, and thus stand out as potential therapeutic targets for modulating fibrin clot formation or dismantling. Here, we review the diversity of serpin-targeting strategies in the area of hemostasis, and detail the suggested use of modified serpins and serpin inhibitors (ranging from small-molecule drugs to antibodies) to treat or prevent bleeding or thrombosis.

Keywords: antithrombin (AT); plasminogen activator inhibitor 1 (PAI-1); protease nexin I (PN-1); protein Z-dependent protease inhibitor (ZPI); serpin (serine proteinase inhibitor); therapy.

Figure 1

Simplified overview of the coagulation and fibrinolysis processes. Coagulation is initiated at site of injury by TF-FVIIa complex that activates FIX and FX. FXa catalyzes thrombin (FIIa) formation, that amplifies its own generation by activating FXI and cofactors FVIII and FV. Thrombin also promotes platelet aggregation and fibrinogen into fibrin conversion to form a stable thrombus. Fibrinolysis is triggered once the clot is formed by tPA-induced plasminogen (plg) activation. The resulting plasmin (pln) enzyme is then responsible of fibrin degradation. The targets of the principal anticoagulant and antifibrinolytic serpins, as well as that of anticoagulant aPC are indicated with color capped arrows.

Figure 2

Mechanism of action of riAT as reversal agent for heparin derivatives anticoagulant activity. (A) In situation of bleeding risk associated with the use of heparin derivatives (yellow), (B) administration of riAT (light pink) could displace heparin derivatives from endogenous AT (red) to riAT by a competition mechanism. (C) Hence, heparins are found trapped in an inactive complex with riAT, reducing thereby their apparent anticoagulant activity.